Spinal cord injury (SCI) is a devastating malady for which there is no cure. The long-term goal of this project is to identify the molecular mechanisms necessary and sufficient to accomplish successful functional recovery after SCI in humans. The ability to regenerate and recover function after injury in the nervous system varies widely across species. The lamprey is a jawless vertebrate with a nervous system that shares many fundamental traits with mammals at the organizational, cellular and molecular levels. However, unlike mammals, lampreys exhibit the remarkable ability to spontaneously regenerate severed axons in their spinal cord and recover function after SCI. As a first step towards our long-term goal, the aims of this project are to obtain the gene expression profile of the central nervous system of uninjured lampreys, and over the time course of their anatomical and functional recovery. These data will provide the essential discovery platform to determine, in an unbiased manner, a set of genes potentially relevant to successful recovery from SCI. Next, as inflammation inhibits recovery from SCI in humans, and little is known about the regulation of inflammation in species that recover after SCI, we will identify immune response genes expressed in lamprey following SCI and over the time course of their anatomical and functional recovery. We will also examine effects on the lamprey's gene expression profile over the time course of anatomical and functional recovery induced by post- SCI treatment with an anti-inflammatory, neuroprotective steroid. By comparison to data obtained from other species, both more and less regenerative, we will identify pathways conserved across regenerative species or absent from less regenerative ones, such as mammals. In summary, this project will provide information critical to generating testable hypotheses on how to promote functional recovery after SCI in biological settings where this remains a challenge, such as in humans. PUBLIC HEALTH RELEVANCE: The long-term goal of this research is to identify molecular factors that promote successful recovery from spinal cord injury (SCI). The goal of this project is to discover the genes expressed during successful anatomical and functional recovery after SCI in the lamprey, an animal that can accomplish this robustly. The insights gained in this study will help us to understand how to promote these processes in other species, such as humans.